Our long range goal is to design and synthesize organic molecules which bind to specific DNA sequences and to covalently modify specific DNA sites. Our first immediate subgoal is to characterize the solution structure of a new DNA conformation we have discovered, a dinucleotide repeat structure which is induced by binding certain steroid diamines to poly(dA-dT). Using NMR and CD to probe DNA conformation we will synthesize new ligands to see what structural features of the steroid diamine promote conformational change in poly(dA-dT). We will chemically synthesize small DNA oligomers to discover what sequences can exist in this new conformation, using NMR as a conformational probe of the DNA-drug complex. We will make DNA with phosphorothioate groups in the backbone to study backbone conformations in detail. Such thio-DNAs will also be used to covalently attach groups to the DNA. We also propose to synthesize new linked drugs containing netropsin and anthramycin fragments. These linked groove binders should exhibit unprecedented sequence selectivity by a synthetic molecule. We will assay selectivity by the drug's differential inhibition of site selectivity of particular restriction enzymes. This work should eventually lead to molecules which can act as repressors of specific genes (incluing oncogenes). It will also provide a way to introduce specific covalent lesions into specific DNA sequences, providing a clean experimental system for determining the mutational properties of DNA backbone alkylation.